Our overall objective is to localize chromosomal loci (and ultimately genes) that predispose to type 2 diabetes by performing a genome wide search using state-of-the-art molecular and statistical genetic approaches in a unique family collection, the Amish Family Diabetes Study. The Old Order Amish are ideal for these studies since they are a closed founder population who are relatively genetically homogeneous, have very large sibship and family sizes, and have well known genealogies. Since February 1995, Dr. Shuldiner has recruited and studied 1,076 Amish individuals from 45 multiplex families. A genome scan (10 centimorgan map; 371 polymorphic short tandem repeat markers) already has been completed in 696 of these subjects. This proposal brings together two strong research groups with complementary interests: Alan Shuldiner, M.D. at the University of Maryland, and Braxton Mitchell, Ph.D. at the Southwest Foundation for Biomedical Research. First, we will perform a genome scan on 380 of our most recently recruited participants of the Amish Family Diabetes Study in order to maximize our power to detect linkages and associations to diabetes and related traits. Second, we will perform a genome-wide linkage analysis, using variance components methods, to identify chromosomal regions containing genes that influence diabetes and related intermediate quantitative phenotypes (e.g., fasting and post-challenge glucose and insulin concentrations, obesity, etc.) in this expanded data set consisting of all 1,076 members of the Amish Family Diabetes Study. We also will perform oligogenic (conditional) analyses to allow for linkage to loci in multiple chromosomal regions in order to strengthen true linkage signals and to reduce false positives, and to examine gene by gene interactions. Third, we will perform genome-wide association analyses, using transmission disequilibrium tests, to test for associations between the offsprings' phenotypes and transmission of specific alleles in the parents. Fourth, in order strengthen linkages/associations and improve localization, we will type additional markers in chromosomal regions showing evidence for linkage and/or association, and perform follow-up analyses, including haplotype sharing analysis. Discovery of type 2 diabetes susceptibility genes will provide (i) critical insights into molecular mechanisms, (ii) new molecular targets for therapeutics, and (iii) blood tests for the early detection of susceptibility individuals so that preventative interventions can be instituted. These advances will impact substantially on the care and quality of life of millions of middle-aged and elderly Americans with type 2 diabetes.